US20240319163A1 - Ovum Evaluation Method, Ovum Evaluation Apparatus, and Ovum Evaluation Program - Google Patents

Ovum Evaluation Method, Ovum Evaluation Apparatus, and Ovum Evaluation Program Download PDF

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US20240319163A1
US20240319163A1 US18/701,534 US202218701534A US2024319163A1 US 20240319163 A1 US20240319163 A1 US 20240319163A1 US 202218701534 A US202218701534 A US 202218701534A US 2024319163 A1 US2024319163 A1 US 2024319163A1
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ovum
evaluation
target
index value
quality
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Motomu Tanaka
Akihisa Yamamoto
Kaori SUGIMURA
Fumitoshi KOGA
Shigeki KITAKAMI
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Koga Fumitoshi Women's Clinic
Shimadzu Corp
Kyoto University NUC
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Koga Fumitoshi Women's Clinic
Shimadzu Corp
Kyoto University NUC
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    • G01—MEASURING; TESTING
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    • C—CHEMISTRY; METALLURGY
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    • C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12M—APPARATUS FOR ENZYMOLOGY OR MICROBIOLOGY; APPARATUS FOR CULTURING MICROORGANISMS FOR PRODUCING BIOMASS, FOR GROWING CELLS OR FOR OBTAINING FERMENTATION OR METABOLIC PRODUCTS, i.e. BIOREACTORS OR FERMENTERS
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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
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Definitions

  • the present invention relates to a method, an apparatus, and a computer program for evaluating the quality of an ovum.
  • In vitro fertilization and intracytoplasmic sperm injection are well known as clinical treatments of assisted reproductive technology in humans.
  • In vitro fertilization is a method in which an ovum taken out from a patient is mixed with sperm (inseminated) to promote fertilization, and the fertilized ovum is cultured for a predetermined period and then transferred to a mother's body (embryo transfer).
  • intracytoplasmic sperm injection is a method in which a fine glass needle called an injection pipette is inserted into an ovum taken out from a patient, and one sperm is injected into the ovum by the injection pipette to perform fertilization. This intracytoplasmic sperm injection is performed by a professional technician (commonly referred to as “embryologist”) under microscopic observation.
  • Patent Literature 1 discloses a technique for quantitatively measuring hardness, which is one of mechanical features of an ovum, from deformation responsiveness, a strain state, a deformation state, or the like of an outer membrane based on local deformation of the ovum observed in an image obtained by photographing the ovum in a state of being pinched by a microprobe.
  • Non Patent Literature 1 mentions that a human embryo that is too hard or too soft when sucked by a manipulator has poor developmental potential.
  • Non Patent Literature 2 discloses a technique in which a micro force sensor using a strain gauge is attached to the tip of a two-fingered micro hand, and measures a reaction force generated at an end effector portion when the two-fingered micro hand grips a cell, to estimate the stiffness of the cell.
  • Non Patent Literature 3 mentions that it has been confirmed that the elasticity of the zona pellucida of an ovum at each stage of ovum maturation, fertilization, and early embryo development specifically changes by using a micro tactile sensor system having a strain gauge at the base of a needle.
  • an invasive method is used to acquire information related to the hardness or elasticity of an ovum for the purpose of evaluating the quality of the ovum.
  • intracytoplasmic sperm injection temporarily holding an ovum and inserting an injection pipette into the ovum at the time of insemination are essential works for treatment.
  • performing an invasive operation on the ovum for other works has a risk of damaging the ovum, which is not preferable.
  • the force may be applied obliquely if the contact points of the sensor deviate from positions facing each other across the center point of the ovum because an ovum is substantially spherical, and the elasticity or the like cannot be accurately measured.
  • the sensor since the sensor does not always contact the same position of the ovum, reproducibility in performing repeated measurements is low.
  • the ovum is usually not perfectly spherical but somehow distorted, it is quite difficult to bring the sensor into contact on an axis passing through the center point of the ovum.
  • the present invention has been made to solve such problems, and a main object of the present invention is to provide an ovum evaluation method, an ovum evaluation apparatus, and an ovum evaluation program capable of evaluating the quality of an ovum accurately according to theoretical criteria on the basis of the result of non-invasive measurement or observation.
  • One mode of an ovum evaluation method according to the present invention made to solve the above problems is a method for evaluating an ovum, the method including:
  • One mode of an ovum evaluation apparatus according to the present invention made to solve the above problems is an apparatus for performing the ovum evaluation method of the above mode according to the present invention, the apparatus including:
  • One mode of an ovum evaluation program according to the present invention made to solve the above problems is a program for evaluating an ovum using a computer, the program causing a computer to execute:
  • the “target ovum” is a subject to be fertilized by in vitro fertilization or intracytoplasmic sperm injection, and is further used for performing embryo transfer through embryo culture after fertilization. For this reason, a work or an operation inevitably performed on the ovum in such assisted reproductive technology, which is a work or an operation in direct contact with the ovum, such as holding of the ovum or insertion of an injection pipette for insemination, performed in, for example, intracytoplasmic sperm injection, does not fall under an invasive work or operation in the present specification and the present invention.
  • the “image” obtained by photographing the target ovum may be an image at a certain time point, that is, a still image, or may be a moving image or time-lapse images composed of a plurality of temporally consecutive images. Therefore, the “deformation state of the target ovum” may be the state of the ovum at a certain time point when the ovum is deformed, or may be the behavior of the ovum during a deformation process of the ovum.
  • the evaluation result by the “evaluation of the quality of the ovum” can include a result indicating whether the quality of one ovum is good or not, a result of ranking the qualities of a plurality of ova, a multi-grade evaluation result corresponding to grade classification used for known evaluation of a fertilized ovum such as Veeck's classification and Gardner's classification, and a determination result indicating whether embryo transfer is suitable or not or whether cryopreservation is suitable or not.
  • such an evaluation result is output as a result of processing in an apparatus (which may include a computer).
  • the evaluation result can correspond to a decision result by an expert embryologist having a high level of skill.
  • the ovum evaluation program of the above mode according to the present invention can be provided to a user by being stored in a non-transitory computer-readable recording medium such as a CD-ROM, a DVD-ROM, a memory card, or a USB memory (dongle).
  • the program can be provided to the user in the form of data transfer via a communication line such as the Internet.
  • the program can be pre-installed in a computer which is a part of the system (strictly, a storage device which is a part of the computer) when the user purchases the system.
  • the quality of the target ovum can be non-invasively evaluated accurately on the basis of the index value obtained by quantifying the mechanical property, that is, with theoretical grounding.
  • the ovum is not damaged during evaluation of the quality of the ovum.
  • the ovum after the evaluation can be favorably used for the original purpose.
  • the present invention reduces the workload of an embryologist, and eliminates a variation in quality evaluation depending on the skill of an embryologist in charge, to improve the reliability of the quality evaluation of the ovum.
  • data in evaluating the quality of the ovum remain as a numerical value, which enables an embryologist or the like to easily and objectively verify whether or not the evaluation is appropriate later.
  • FIG. 1 is a flowchart illustrating an example of a work/processing procedure in intracytoplasmic sperm injection using an embodiment of an ovum evaluation method according to the present invention.
  • FIG. 2 is a flowchart illustrating a detailed processing procedure of ovum evaluation processing before insemination in the work/processing procedure of intracytoplasmic sperm injection illustrated in FIG. 1 .
  • FIG. 3 is a schematic configuration diagram of an example of an ovum evaluation apparatus for performing ovum evaluation processing before insemination and ovum evaluation processing during insemination.
  • FIG. 4 is a drawing illustrating an example of an image obtained by photographing an ovum in the ovum evaluation apparatus.
  • FIG. 5 is a drawing illustrating an actual measurement result of a luminance profile on line U illustrated in FIG. 4 .
  • FIGS. 6 A- 6 C are explanatory views of a process of averaging luminance values of points on line U.
  • FIG. 7 is a drawing illustrating a relationship between an angle ⁇ and a radius r( ⁇ ) of an ovum.
  • FIG. 8 is a drawing illustrating a mean square amplitude (MSA) value of a radius calculated from actual measurement data and a fitting curve using a theoretical formula.
  • MSA mean square amplitude
  • FIG. 9 is an explanatory view of a method for calculating an aspect ratio of a deformed ovum at the time of insertion of an injection pipette.
  • FIGS. 10 A and 10 B are drawings illustrating a deformation state of an ovum at the time of fixation by a holding pipette.
  • FIG. 11 is an explanatory view on how to obtain an index value of deformation relaxation of an ovum after a time point of opening a hole by insertion of an injection pipette.
  • FIG. 12 is a drawing illustrating a temporal change in deformation relaxation of an ovum after a time point of opening a hole by insertion of an injection pipette.
  • FIGS. 13 A and 13 B are explanatory views on how to obtain the internal area of an ovum at the time of insertion of an injection pipette.
  • FIG. 1 is a flowchart illustrating a series of work/processing procedure in intracytoplasmic sperm injection using the embodiment of the ovum evaluation method according to the present invention.
  • FIG. 2 is a flowchart illustrating a detailed processing procedure of ovum evaluation processing before insemination in the work/processing procedure of intracytoplasmic sperm injection illustrated in FIG. 1 .
  • FIG. 3 is a schematic configuration diagram of the embodiment of the ovum evaluation apparatus according to the present invention for performing ovum evaluation processing before insemination and ovum evaluation processing during insemination illustrated in FIG. 1 .
  • the ovum evaluation method and the ovum evaluation apparatus of the present embodiment are mainly for evaluating the quality of an ovum and choosing a high-quality ovum in performing intracytoplasmic sperm injection which is one of assisted reproductive technologies.
  • some approaches of the ovum evaluation method of the present embodiment can also be used to evaluate and choose an ovum in order to perform in vitro fertilization instead of intracytoplasmic sperm injection.
  • a doctor When intracytoplasmic sperm injection is performed, first, a doctor performs ovum retrieval from a patient. Usually, a plurality of ova are retrieved from the patient (step S 1 ).
  • an embryologist collectively or individually sets the plurality of retrieved ova in the ovum evaluation apparatus, which will be described later, and performs a predetermined operation in the apparatus.
  • the ovum evaluation apparatus performs ovum evaluation processing before insemination as first-stage ovum evaluation on the plurality of ova (step S 2 ).
  • the embryologist selects one or more ova to be subjected to an intracytoplasmic sperm injection work on the basis of the evaluation result by the ovum evaluation apparatus (step S 3 ).
  • the embryologist performs an insemination work while observing the selected ovum with a microscope.
  • the above ovum evaluation apparatus photographs a moving image of the state of the ovum during the insemination work (step S 4 ).
  • the embryologist performs a predetermined operation in the above ovum evaluation apparatus.
  • the ovum evaluation apparatus performs ovum evaluation processing during insemination as second-stage ovum evaluation on the basis of the image photographed during the insemination work (step S 5 ).
  • the embryologist selects one or more ova (fertilized ova) to be cultured (or cryopreserved) on the basis of the evaluation result by the ovum evaluation apparatus (step S 6 ).
  • the embryologist cultures the selected fertilized ovum (ova) for a predetermined period, and after the culture, the doctor transfers an embryo obtained by the culture to the patient (step S 7 ).
  • the embryologist cryopreserves the fertilized ovum (ova) after being cultured for a predetermined period.
  • the quality of the ovum is evaluated in each of two stages of before insemination and during insemination using the ovum evaluation apparatus, which secures the quality of the fertilized ovum to be transferred to the patient.
  • Both of these two stages of ovum evaluation are evaluation before the fertilized ovum is accommodated in an incubator, and it is possible to choose an ovum having a high fertilization success rate at an early stage.
  • a culture loss can be reduced by efficiently choosing the fertilized ovum to be accommodated in the incubator having a limited capacity.
  • the turnover rate of the incubator can be improved to reduce the number of standby patients for infertility treatment.
  • the ovum evaluation apparatus includes a microscopic observation unit 1 including an image acquiring unit 10 , a photographing control unit 2 , a data processing unit 3 , a main control unit 4 , an input unit 5 , and a display unit 6 .
  • the data processing unit 3 includes, as functional blocks, an image data storage 30 , a contour extractor 31 , a radius calculator 32 , a radial displacement amount calculator 33 , a mechanical parameter calculator 34 , a first evaluator 35 , an aspect ratio calculator 36 , and a second evaluator 37 .
  • the first evaluator 35 performs classification or regression by machine learning, and includes a learned model storage 350 that stores a learned model trained in advance using training data for this purpose.
  • the microscopic observation unit 1 may be either a bright field microscope or a phase contrast microscope.
  • the image acquiring unit 10 may acquire either a color image or a monochrome image.
  • the image acquiring unit 10 may be a video camera capable of photographing a moving image at a general frame rate (60 frames/second), or may be a camera that performs time-lapse imaging at predetermined time intervals at a moderately reduced frame rate.
  • At least some functions of the data processing unit 3 and the main control unit 4 can include a computer such as a personal computer as a hardware resource, and control/processing software (program) installed in advance in the computer is executed on the computer to implement operations of the above respective functional blocks.
  • the input unit 5 and the display unit 6 are a keyboard or a pointing device (such as a mouse), and a monitor, respectively, attached to the personal computer.
  • This computer program is an embodiment of an ovum evaluation program according to the present invention.
  • the embryologist (or another person in charge) sets a target ovum 100 to be evaluated on a stage of the microscopic observation unit 1 so that its polar body does not appear in the image, and performs an operation of giving an instruction to start analysis from the input unit 5 .
  • the photographing control unit 2 operates the image acquiring unit 10 to photograph a moving image of the ovum 100 over a predetermined time (for example, about 30 seconds) (step S 20 ).
  • the moving image data obtained by the image acquiring unit 10 is transferred to the data processing unit 3 and temporarily stored in the image data storage 30 .
  • the contour extractor 31 executes a process of extracting the contour of the ovum in each frame image of the moving image (step S 21 ). Specifically, the contour extractor 31 performs the following processing.
  • the contour extractor 31 first performs noise removal processing using a Gaussian filter, a median filter, or the like as preprocessing on each frame image.
  • FIG. 4 is an example of the photographed image of the ovum.
  • the ovum egg cell
  • the above noise removal processing is processing for removing fine salt-and-pepper noise generated in the vicinity of the zona pellucida and the cell membrane on the image.
  • the contour extractor 31 subsequently obtains, for each frame image, a luminance profile indicating a change in luminance values of pixels along a straight line extending outward (or pixels at predetermined intervals) from the center point of the ovum.
  • FIG. 5 is a luminance profile on straight line U illustrated in FIG. 4 .
  • the center point of the ovum can be obtained by, for example, approximation of center coordinates of a circle using a least squares method (by calculating the center of a circle from contour coordinates).
  • the ovum may be irradiated with strong illumination light.
  • strong light may damage the ovum.
  • this noise can be an error factor in extracting the contour from the luminance profile. Therefore, in order to eliminate the luminance noise, the contour extractor 31 executes smoothing processing in which the luminance value of each point (pixel) on the luminance profile is replaced with a value obtained by averaging the luminance values of a total of five points including two points in front of the point and two points behind the point.
  • FIGS. 6 A- 6 C are explanatory views of the smoothing processing.
  • the luminance values of five consecutive points on straight line U are x i ⁇ 2 , x i ⁇ 1 , x i , x i+1 , and x i+2 as illustrated in FIG. 6 A
  • the contour extractor 31 selects a maximum value (or a minimum value) among differential values as a point on the contour in the luminance profile after the smoothing processing along a plurality of straight lines extending radially in different directions from the center point of the ovum.
  • the contour of the target ovum can be accurately extracted by obtaining the point on the contour in each of the straight lines drawn at predetermined angular intervals in an angular range of 360° around the center point of the ovum, and connecting the points together.
  • Non Patent Literature 4 written by some of the present inventors discloses that the contour of a red blood cell having a shape close to a circle is extracted from an image of the red blood cell to obtain a radius (a distance from the center point to the contour).
  • the present inventors have studied whether the same method can be applied to an ovum. However, it is difficult to directly apply the same method. The reason is that, in the case of a red blood cell, the curve shape of the luminance profile is smooth and the contour appears quite clearly, whereas in the case of an ovum, a large amount of noise is included particularly around the cell membrane due to a thick zona pellucida existing outside the cell membrane, which makes it difficult to extract the contour.
  • the contour extractor 31 first calculates the luminance profiles along radial straight lines in 64 directions at (360/64°) angular intervals around the center point of the ovum, and roughly extracts a range corresponding to the contour in the luminance profiles. After that, while gradually narrowing a calculation range of the luminance profiles in the radial direction to a range estimated to include the contour, the contour extractor 31 repeats similar calculation 3 times along radial straight lines in 256 directions at (360/256°) angular intervals around the center point of the ovum, to finally obtain the contour with high accuracy.
  • the contour extractor 31 similarly extracts the contour of the ovum for the images of all the frames constituting the moving image over the predetermined time.
  • the radius calculator 32 obtains a radius (strictly speaking, a distance from the center point to the contour) in each of directions at predetermined angular intervals ⁇ around the center point of the ovum for each frame image (step S 22 ). That is, as illustrated in FIG. 7 , a radius r( ⁇ ) is calculated for a plurality of predetermined angles ⁇ .
  • the center point at the time of calculating the radius may be a gravity center position calculated from the contour.
  • the shape of the ovum which is one type of cell, temporally changes due to fluctuation.
  • the radial displacement amount calculator 33 calculates a radial displacement amount reflecting the shape fluctuation of the ovum on the basis of the information of an enormous number of radii for each frame image (step S 23 ).
  • the method disclosed in Non Patent Literature 4 is used here.
  • the radial displacement amount calculator 33 calculates a mean square amplitude (MSA) that is a function of a wavenumber q by performing a Fourier transform operation using the following Formula (1).
  • MSA mean square amplitude
  • ⁇ > represents a temporal mean through all the frames.
  • Formula (1) can be considered that a difference between the radius and the temporal mean of the radii is obtained for each direction, and a temporal change of a value obtained by adding the differences in all the directions is regarded as the function of the wavenumber by Fourier transform.
  • FIG. 8 the mean square amplitude values calculated by the above procedure on the basis of actual measurement data are plotted.
  • q x is a continuous wavenumber corresponding to experimental q.
  • L is the length in one dimensional direction of a cell (here, an ovum).
  • KB is a Boltzmann constant
  • T is an absolute temperature at the time of an experiment.
  • Other parameters ⁇ , ⁇ , and ⁇ are unknown mechanical parameters, where ⁇ is a spring constant, ⁇ is surface tension, and ⁇ is bending elasticity.
  • the mechanical parameter calculator 34 calculates the three unknown mechanical parameters by fitting Formula (2) to the mean square amplitudes calculated from the actual measurement data as described above (step S 24 ). In FIG. 8 , a curve in performing the fitting is indicated by a solid line.
  • These three mechanical parameters are index values reflecting the mechanical properties of the ovum, that is, hardness and softness. That is, the mechanical properties of the ovum are quantified in this manner.
  • the first evaluator 35 obtains information on the quality of the ovum from the mechanical parameter values of the ovum calculated as described above (step S 25 ).
  • a machine learning method is used to evaluate the quality. That is, the first evaluator 35 determines whether the quality of the ovum is good or not by performing classification using a learned model based on a predetermined machine learning algorithm, in which the above three mechanical parameter values are input, and an evaluation result is output in which an ovum with good quality is “1” and an ovum with poor quality is “0”.
  • the learned model is created in advance (for example, at a stage before shipment of the apparatus by a manufacturer) as follows.
  • the mechanical parameters of each ovum are obtained according to the procedure as described above.
  • a skilled embryologist evaluates the quality of each ovum during a process of performing normal insemination and subsequent culture of the ova, and leaves the evaluation result.
  • the evaluation result by the embryologist may be binary information indicating whether the quality is good or not, such as the suitability of transfer and the suitability of cryopreservation.
  • the evaluation result may also be multi-value information according to a known multi-grade evaluation method such as Veeck's classification and Gardner's classification.
  • a known multi-grade evaluation method such as Veeck's classification and Gardner's classification.
  • the learned model storage 350 stores this learned model.
  • the work of creating the learned model on the basis of the training data as described above may be performed by a user, but is usually performed by a manufacturer of the present apparatus or a manufacturer providing software.
  • the first evaluator 35 When evaluating an unknown ovum, the first evaluator 35 receives mechanical parameter values obtained for the unknown ovum as input to the learned model, to be able to output a result indicating whether the quality of the ovum is good or not. This evaluation result is output from the display unit 6 through the main control unit 4 .
  • the first evaluator 35 may use a machine learning algorithm for binary classification.
  • the correct answer data is binary data, it is possible to calculate a probability of the quality being good as a numerical value by using a machine learning algorithm for regression analysis such as logistic regression, for example. Therefore, in this case, for example, by comparing the calculated probability with a threshold value, it is possible to determine whether the quality of the ovum is good or not.
  • the first evaluator 35 can obtain the evaluation result of the quality of the ovum as the numerical value such as the fertilization rate and the implantation rate. Also in this case, the first evaluator 35 determines whether or not the numerical value of the probability output as the evaluation result is a predetermined threshold value or more, so that the result indicating whether the quality of the ovum is good or not can be obtained and displayed on the display unit 6 .
  • a numerical value of the probability may be displayed together with the quality determination result, or only the numerical value of the probability may be displayed.
  • the first evaluator 35 can rank a plurality of ova retrieved from one patient on the basis of the numerical value and display the result of ranking on the display unit 6 .
  • the embryologist (doctor) who has confirmed this result can choose an ovum to be subjected to intracytoplasmic sperm injection from the plurality of ova or can select an appropriate ovum to be returned to the patient's body with reference to the ranking.
  • a multi-grade evaluation method such as the Veeck's classification and the Gardner's classification described above are well known.
  • the Veeck's classification is an index for evaluating the quality of an early embryo on Day 2 to Day 4 of culture in an ovum after insemination, and is classification with five grades.
  • the Gardner's classification is an index for evaluating the state of a blastocyst on Day 5 to Day 6 of culture, and is classification with six grades.
  • a learned model may also be created by performing learning using training data in which a result of grading in the Veeck's classification or the Gardner's classification is used as correct answer data, and the result of grading in the Veeck's classification or the Gardner's classification may be obtained from mechanical parameter values for an ovum before insemination using this learned model.
  • the mechanical parameters of the ovum may be used as an evaluation index, but also various information other than the mechanical parameters related to the ovum, for example, other information such as the size of the ovum may be added as the evaluation index.
  • other information such as the size of the ovum may be added as the evaluation index.
  • information specific to a patient for example, information such as the age, past results of artificial insemination, and medical history of the patient may be added as the evaluation index.
  • the age of a patient greatly affects the quality of an ovum.
  • the age may be treated as the input of the learned model equivalent to the mechanical parameters, but instead, a result obtained by machine learning, for example, a threshold value on up to what rank is determined to be good in quality in the result of ranking a plurality of ova, a threshold value on what percentage or more is determined to be good in quality with regard to the probability of the quality being good, and the like may be changed according to the age of the patient.
  • the present inventors have experimentally verified whether or not an ovum retrieved from an actual patient can be accurately evaluated using the learned model created so as to evaluate the quality of an ovum from the viewpoint of the suitability of transfer into a mother's body.
  • quality evaluation based on actually-measured mechanical parameters has been performed for a plurality of ova retrieved per patient from 14 patients.
  • it has been possible to confirm that the result of the evaluation using the learned model is almost equivalent to the evaluation of the quality of the ovum by a skilled embryologist.
  • the embryologist refers to the evaluation result, selects one or more good-quality ova from a plurality of ova retrieved from one patient, and discards the others. Then, the embryologist performs an operation of intracytoplasmic sperm injection on the selected good-quality ovum (ova).
  • the method of intracytoplasmic sperm injection is exactly the same as the conventional method, in which the embryologist injects sperm by inserting an injection pipette into the ovum while observing the ovum with a microscope.
  • this intracytoplasmic sperm injection work is performed under observation by the microscopic observation unit 1 of the ovum evaluation apparatus illustrated in FIG. 3 .
  • the image acquiring unit 10 photographs the state of the ovum during the work, particularly the state of the ovum from a time point immediately before the injection pipette is inserted into the ovum until a predetermined time elapses after the injection pipette is removed.
  • the obtained moving image data is transferred to the data processing unit 3 and temporarily stored in the image data storage 30 .
  • the embryologist (or another person in charge) performs a predetermined operation on the input unit 5 .
  • the data processing unit 3 performs the ovum evaluation processing during insemination as the second-stage ovum quality evaluation on the basis of the stored moving image data.
  • This ovum evaluation will be described in detail with reference to FIG. 9 .
  • the operation of inserting the injection pipette into the ovum is an essential operation for intracytoplasmic sperm injection, and is not an operation involving contact with or invasion upon the ovum other than the normal operation. Thus, it can be said that this ovum evaluation is also non-invasive evaluation.
  • FIG. 9 is an image showing the state of the ovum when the injection pipette is inserted into the ovum for intracytoplasmic sperm injection.
  • the ovum is fixed by a holding pipette.
  • the tip of the injection pipette is pierced through the zona pellucida of the fixed ovum and is further pierced through the cell membrane of the ovum to be pushed deep into the ooplasm.
  • the sperm is injected into the ooplasm and then the injection pipette is quickly withdrawn from the ovum.
  • the tip of the injection pipette is pierced into the zona pellucida, the zona pellucida is pushed by the tip of the injection pipette to be once recessed inward.
  • the aspect ratio calculator 36 detects, from the stored moving image, an image in a state where the zona pellucida is deformed the most immediately before the deformation starts to be relaxed after the zona pellucida is greatly deformed at the time of insertion of the injection pipette as described above.
  • the aspect ratio calculator 36 calculates the length in a minor axis direction and the length in a major axis direction of the zona pellucida from the image, and obtains the ratio of the lengths as an aspect ratio.
  • the length in the minor axis direction is the width of the zona pellucida at a position passing through substantially the center of the ovum along an advancing and retracting direction (horizontal direction in FIG.
  • the length in the major axis direction is the width of the zona pellucida at a position passing through substantially the center of the ovum along a direction (vertical direction in FIG. 9 ) orthogonal to the advancing and retracting direction of the injection pipette.
  • the above aspect ratio of the zona pellucida which is a part of the ovum, is affected by the mechanical properties of the zona pellucida, specifically, the elasticity.
  • the above aspect ratio is a useful index for measuring the mechanical properties of the ovum, and the mechanical properties of the ovum affect the quality of the ovum.
  • the quality of the ovum can be evaluated on the basis of the aspect ratio. Therefore, the second evaluator 37 receives the value of the above aspect ratio and compares the value with a predetermined threshold value to determine whether the quality of the ovum is good or not. Then, the determination result of the quality of the ovum is displayed on the display unit 6 through the main control unit 4 .
  • the quality of the ovum may be evaluated together with an index other than the aspect ratio, for example, personal information such as the age of the patient.
  • the aspect ratio of not the zona pellucida but the cell membrane that is, the aspect ratio in a state where the cell membrane is deformed the most immediately before the deformation starts to be relaxed after the cell membrane is greatly deformed at the time of insertion of the injection pipette, may be calculated, and the quality of the ovum may be determined using this aspect ratio.
  • the quality of the ovum may be determined using both the aspect ratio of the zona pellucida and the aspect ratio of the cell membrane.
  • the quality may be determined to be poor in the ovum evaluation during insemination.
  • the fertilization rate or the implantation rate is possibly poor. Therefore, by excluding the fertilized ovum evaluated to be poor in quality during insemination from a culture target, the culture loss of the fertilized ovum can be reduced, and the incubator can be effectively used.
  • the aspect ratio at the time of maximum deformation of the zona pellucida and/or the cell membrane is used as the ovum evaluation during insemination.
  • the quality of the ovum can also be evaluated using other information as described below reflecting the mechanical properties of the cell membrane or the zona pellucida.
  • FIGS. 10 A and 10 B are examples of images showing the state of the ovum fixed by the holding pipette.
  • the cell membrane is deformed so as to protrude clearly by being sucked by the holding pipette.
  • the cell membrane hardly protrudes although being sucked by the holding pipette.
  • This difference in deformation reflects a difference in the elasticity of the ovum. Therefore, the second evaluator 37 can determine whether the quality of the ovum is good or not by determining the presence or absence of deformation by image processing, for example.
  • the deformation amount may be quantified, and the quantitative value may be compared with a threshold value to determine whether the quality of the ovum is good or not.
  • the second evaluator 37 can obtain, from the moving image acquired during the insemination work, a time required for the deformation of the cell membrane to be relaxed (return to the original state) (hereinafter, referred to as “relaxation time”) from a moment when the injection pipette pierces the cell membrane, to determine whether the quality of the ovum is good or not on the basis of the relaxation time.
  • FIG. 11 is a drawing illustrating a portion to observe a change in the cell membrane in obtaining an index value of deformation relaxation of the ovum after a time point of opening a hole by insertion of the injection pipette.
  • FIG. 12 is a drawing illustrating an example of a temporal change in deformation of the cell membrane (deformation relaxation of the ovum) after being pierced by the injection pipette.
  • FIG. 11 is an image showing a state immediately before the tip of the injection pipette pierces the cell membrane.
  • x 1 is a distance from the tip position of the injection pipette immediately before a hole is opened in the cell membrane to the position of the cell membrane facing the tip ahead of the tip.
  • x 2 is the depth of a recess in the cell membrane formed by being pressed by the injection pipette.
  • x 3 is the diameter of the rim of the recess in the cell membrane formed by being pressed by the injection pipette. All of these values indicate maximum values immediately before the tip of the injection pipette pierces the cell membrane, and decrease with time after the piercing.
  • the data processing unit 3 calculates x 1 , x 2 , and x 3 after the time point when the tip of the injection pipette pierces the cell membrane in the frame images at predetermined time intervals included in the moving image.
  • the actually-measured values change as plotted in FIG. 12 , for example. Therefore, the second evaluator 37 calculates a relaxation time ti by fitting Formula (3) which is a theoretical formula to the actually-measured values:
  • the quality of the ovum may be evaluated using the relaxation time of at least one size of x 1 , x 2 , and x 3 illustrated in FIG. 11 .
  • the quality of the ovum may be evaluated using at least one size of x 1 , x 2 , and x 3 at the time point when the cell membrane is deformed the most as the evaluation index.
  • FIG. 13 A is a drawing illustrating a portion surrounded by the zona pellucida
  • FIG. 13 B is a drawing illustrating a portion surrounded by the cell membrane in the image of the ovum.
  • a change in the area of each of the above portions when the zona pellucida or the cell membrane is deformed the most immediately before the tip of the injection pipette pierces the cell membrane or the area of each of the above portions during deformation relaxation after the moment when the tip of the injection pipette pierces the cell membrane also reflects the elasticity of the ovum. Therefore, it is also possible to evaluate the quality of the ovum by using such information as the evaluation index.
  • the evaluation of the quality of the ovum by the first evaluator 35 and the evaluation of the quality of the ovum by the second evaluator 37 are completely independent of each other, it is obvious that only one of them may be performed. Of course, it is obviously very convenient to use both in intracytoplasmic sperm injection because it is possible to narrow down the ova to be fertilized and to narrow down the ova (fertilized ova) to be cultured. In addition, it goes without saying that the evaluation of the quality of the ovum by the first evaluator 35 is also useful in choosing the ovum to be subjected to in vitro fertilization instead of intracytoplasmic sperm injection.
  • both the ovum evaluation before insemination and the ovum evaluation during insemination can be performed. However, these can be performed in separate apparatuses.
  • the ovum evaluation apparatus outputs the evaluation result or the determination result of the quality of the set ovum, and the embryologist selects an ovum with reference to the evaluation result or the determination result.
  • the final selection/choosing of the ovum may be decided by an embryologist, or the selection/choosing of the ovum may be automatically performed without such decision.
  • One mode of an ovum evaluation method according to the present invention is a method for evaluating an ovum, the method including:
  • One mode of an ovum evaluation apparatus includes:
  • One mode of an ovum evaluation program according to the present invention is a program for evaluating an ovum using a computer, the program causing a computer to execute:
  • the quality of the target ovum can be non-invasively evaluated accurately on the basis of the index value obtained by quantifying the mechanical property, that is, with theoretical grounding.
  • the ovum is not damaged during evaluation of the quality of the ovum.
  • the ovum after the evaluation can be favorably used for the original purpose.
  • the workload of an embryologist is reduced, and a variation in quality evaluation depending on the skill of an embryologist in charge is eliminated, to improve the reliability of the quality evaluation of the ovum.
  • data in evaluating the quality of the ovum remain as a numerical value, which makes it easy for an embryologist or the like to verify whether or not the quality evaluation is appropriate later.
  • the target ovum may be an ovum before insemination
  • the image may be a moving image or time-lapse images of the target ovum
  • the target ovum may be an ovum before insemination
  • the image may be a moving image or time-lapse images of the target ovum
  • the shape of the ovum which is one type of cell, temporally changes due to fluctuation.
  • the mode of the shape change of the ovum due to fluctuation is affected by elasticity reflecting the hardness or the like of the ovum.
  • the change in the shape of the ovum is obtained as the information of the displacement amount of the contour in the contour extraction step and the displacement amount acquisition step.
  • the mechanical parameter calculation step the mechanical parameter of the ovum is calculated from the information of the displacement amount of the contour.
  • the mechanical parameter in the mechanical parameter calculation step, the mechanical parameter may be obtained by performing parameter fitting using a theoretical formula representing elasticity of a cell.
  • the mechanical parameter calculation processor may be configured to obtain the mechanical parameter by performing parameter fitting using a theoretical formula representing elasticity of a cell, on an actually-measured value representing the displacement amount of the contour of the target ovum.
  • the quality of the ovum may be evaluated using a discriminator obtained by machine learning using training data including an evaluation result of an ovum by an embryologist in at least any of stages from fertilization to implantation or training data in which information of a probability of success or failure in any of the stages is known.
  • the evaluator may be configured to evaluate the quality of the ovum using a discriminator created in advance by machine learning using training data including an evaluation result of an ovum by an embryologist in at least any of stages from fertilization to implantation or training data in which information of a probability of success or failure in any of the stages is known.
  • any machine learning algorithm may be used.
  • the ovum evaluation method and the ovum evaluation apparatus of the fourth mode it is possible to accurately evaluate an ovum before culture by reflecting a decision result of the suitability of transfer of a fertilized ovum or the like by an expert embryologist having a high level of skill.
  • the quality of the ovum can be accurately evaluated by reflecting past success/failure results such as a fertilization rate and an implantation rate.
  • the quality of the ovum may be evaluated using patient-specific information including an age in addition to the index value.
  • the evaluator may be configured to evaluate the quality of the ovum using patient-specific information including an age that is input in advance in addition to the index value.
  • the fertilization rate and the implantation rate decrease as the age of a patient increases.
  • the influence of the increase in the age of a patient appears in a decrease in the elasticity of an ovum, but other factors that have not yet been sufficiently elucidated are also conceivable.
  • the patient-specific information such as an age is additionally considered in the evaluation, which makes it possible to more accurately evaluate the quality of the ovum and increase the possibility of pregnancy.
  • the evaluator may be configured to rank a plurality of ova using information on the quality of the ovum obtained for each of the plurality of ova.
  • an operation of intracytoplasmic sperm injection can be performed on one ovum estimated to have the highest probability of pregnancy or a small number of ova estimated to have a relatively high possibility of pregnancy among the plurality of ova retrieved from the patient.
  • one estimated to have the highest probability of pregnancy can be chosen and transferred, and the rest can be cryopreserved.
  • the image may be an image photographed when a needle is inserted into the target ovum for intracytoplasmic sperm injection, and
  • the image may be an image photographed when a needle is inserted into the target ovum for intracytoplasmic sperm injection, and
  • the quality of the ovum is evaluated from the index value calculated on the basis of the image photographed when the intracytoplasmic sperm injection is performed. As described above, it can be said that the evaluation of the quality of the ovum is performed non-invasively in that special invasive measurement or observation for evaluating the quality of the ovum is not performed.
  • ovum evaluation method and the ovum evaluation apparatus of the seventh mode quantitative evaluation using a specific numerical value can be performed instead of sensory and qualitative evaluation such as being elastic or being poorly elastic, which has been conventionally performed by an embryologist at the time of performing intracytoplasmic sperm injection. This improves the accuracy and reliability of the evaluation of the quality of the ovum. Furthermore, data in evaluating the quality of the ovum remain as a numerical value, and the accuracy of the evaluation or the like can be easily verified.
  • the index value reflecting the degree of deformation in the maximum deformation may be a ratio of widths in two directions of a needle insertion direction and a direction orthogonal to the needle insertion direction in the maximum deformation of the zona pellucida or the cell membrane of the target ovum.
  • the index value reflecting the degree of deformation in the maximum deformation may be a ratio of widths in two directions of a needle insertion direction and a direction orthogonal to the needle insertion direction in the maximum deformation of the zona pellucida or the cell membrane of the target ovum.
  • the quality of the ovum can be accurately evaluated on the basis of the index value accurately reflecting the degree of elasticity of the ovum at the time of intracytoplasmic sperm injection.
  • An ovum evaluation method may further include a choosing step of choosing an ovum using an evaluation result in the evaluation step.
  • the load of an ovum choosing work by an embryologist is reduced.
  • the ovum can be chosen on the basis of the evaluation result having theoretical grounding rather than sensory evaluation, and the reliability of choosing is improved.
  • the quality of the ovum which is an ovum before insemination may be evaluated in the analysis step and the evaluation step, the method further including:
  • an ovum evaluation apparatus may further include:
  • the quality of the ovum is evaluated by, for example, the ovum evaluation method of the second mode, the ovum is chosen on the basis of the result, and then intracytoplasmic sperm injection is performed on the chosen ovum, the quality of the ovum can be evaluated again by the ovum evaluation method of the seventh mode.
  • the accuracy and reliability of the evaluation can be improved, and the possibility of pregnancy can be increased.

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